Arthritic alphaviruses, such as Chikungunya virus (CHIKV) and Ross River virus (RRV) cause severe acute and persistent arthritis and myositis in infected humans and are significant emerging disease threats. A growing body of evidence suggests that CHIKV and related viruses have a complex interplay with the host innate immune response, where the type I IFN system is required for control of viral replication, but an overactive host inflammatory response contributes to virus-induced disease. Therefore, in order to develop new therapeutic approaches for these important human pathogens, it is essential that we have a better understanding of how these pathogens interact with the innate immune system. Tripartite motif- containing (TRIM) family members are key players in the host innate immune system, where TRIMs can act as antiviral effector molecules, modulate the type I IFN induction/signaling pathway, or regulate the host inflammatory response. We were interested in determining whether TRIM family members contribute to the control or exacerbation of alphavirus-induced inflammatory arthritis and found that several TRIM family members, including TRIM21 and TRIM34 were significantly upregulated in the joints of mice suffering from either RRV or CHIKV- induced arthritis. Furthermore, a combination of over expression assays and siRNA mediated knockdown studies indicate that both TRIM21 and TRIM34 have antiviral activity against CHIKV and RRV, but not against two other alphaviruses, Sindbis virus and Venezuelan equine encephalitis virus (VEEV), suggesting that TRIM21 and TRIM34 specifically interact with a subset of related alphaviruses. Based on these preliminary results, we propose to utilize a combination of in vitro and in vivo approaches to investigate the mechanism(s) by which TRIM21 and TRIM34 inhibit CHIKV/RRV replication and assessTRIM21's role in regulating the CHIKV induced inflammatory response in a mouse model of CHIKV-induced arthritis. These studies will elucidate the mechanisms underlying the anti-alphavirus activities of TRIM21 and TRIM34, shed new light on the mechanisms regulating alphavirus-induced arthritis, and may ultimately lead to the development of new therapies aimed at inhibiting the replication of CHIKV and related viruses or modulating the virus-induced inflammatory response. Relevance: Arthritic alphaviruses such as chikungunya virus (CHIKV) and Ross River virus (RRV) are significant emerging disease threats, yet we know relatively little about how these viruses induce disease or how the host innate immune response controls their spread. The proposed studies, which will evaluate the role of tripartite motif-containing (TRIM) family members in controlling CHIKV and RRV replication and the virus-induced inflammatory response, have the potential to expand our understanding of how arthritic alphaviruses interact with the host innate immune system and may identify new targets for therapeutic intervention.